Time-dependent effect of p-Aminophenol (PAP) toxicity in renal slices and development of oxidative stress

Harmon, R. Christopher; Terneus, Marcus; Kiningham, Kinsley K.; Valentovic, Monica

doi:10.1016/j.taap.2005.03.011

Cited by 28 publications

(25 citation statements)

References 24 publications

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“…These reactive intermediates may be responsible for mitochondrial damage and covalent binding observed with PAP (Crowe et al, 1977(Crowe et al, , 1979Kruidering et al, 1994). However, PAP has also been shown to cause lipid peroxidation, measured as 4-hydroxynonenal-adducted proteins (Harmon et al, 2005(Harmon et al, , 2006. The ability of PAP to generate reactive oxygen intermediates has not been investigated previously.…”

Section: Discussionmentioning

confidence: 99%

“…co-workers (2005, 2006) observed formation of 4-hydroxynonenal-adducted proteins when rat renal cortical slices were incubated with PAP, suggesting that lipid peroxidation accompanied toxicity. GSH depletion occurred following PAP exposure in both in vitro (Harmon et al, 2005) and in vivo studies (Shao and Tarloff, 1996), suggesting that PAP induced oxidative stress. Reactive oxygen intermediates (ROS), such as superoxide anion, may be generated during oxidative stress (Harmon et al, 2005).…”

Section: Introductionmentioning

confidence: 95%

“…GSH depletion occurred following PAP exposure in both in vitro (Harmon et al, 2005) and in vivo studies (Shao and Tarloff, 1996), suggesting that PAP induced oxidative stress. Reactive oxygen intermediates (ROS), such as superoxide anion, may be generated during oxidative stress (Harmon et al, 2005). While covalent binding of radiolabel from PAP has been reported (Crowe et al, 1979), the ability of PAP to generate ROS has not been investigated previously.…”

Section: Introductionmentioning

confidence: 95%

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Contribution of reactive oxygen species to para-aminophenol toxicity in LLC-PK1 cells

Foreman¹,

Tarloff²

2008

Toxicology and Applied Pharmacology

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Para-aminophenol (PAP) causes nephrotoxicity by biochemical mechanisms that have not been fully elucidated. PAP can undergo enzymatic or non-enzymatic oxidation to form reactive intermediates. Using modulators of reactive oxygen species (ROS), the role of ROS in PAP toxicity in LLC-PK 1 cells was investigated. ROS formation was determined using a fluorescein derivative and viability using alamarBlue. Following treatment of cells with PAP, ROS formation occurred prior to loss of cell viability. Several modulators of ROS were used to identify the pathways involved in PAP toxicity. Viability was improved with catalase treatment, while viability was decreased when cells were treated with superoxide dismutase (SOD). Both catalase and SOD exert their effects outside of cells in the incubation medium, since there was no evidence of uptake of these enzymes in LLC-PK 1 cells. In cell-free incubations, hydrogen peroxide (H 2 O 2 ) was produced when 0.5 mM PAP was included in the incubation medium. Further, SOD greatly increased and catalase greatly decreased H 2 O 2 production in these cell-free incubations. These data suggest that H 2 O 2 formed in the incubation medium contributes to loss of viability following PAP treatment. When cells were coincubated with 0.5 mM PAP and tiron, pyruvate, bathocuproine, 1, 10-phenanthroline, or dimethylthiourea (DMTU), ROS formation was decreased. However, there was minimal improvement in cell viability. Paradoxically, DMTU exacerbated PAP-induced loss of viability. These data suggest ROS are generated in cells exposed to PAP but these species are not the predominant cause of cellular injury.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 95%

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Contribution of reactive oxygen species to para-aminophenol toxicity in LLC-PK1 cells

Foreman¹,

Tarloff²

2008

Toxicology and Applied Pharmacology

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“…The rapid dilation of tubules in the low dose has been attributed to a sudden increase in intratubular pressure (Davis et al, 1983). This pattern of lesion distribution along with dose responsiveness is characteristic of the analgesic model of ATN (Newton et al, 1983;Fowler et al, 1991;Harmon et al, 2005).…”

Section: Histopathologymentioning

confidence: 98%

“…35, No. 4, 2007 MARKERS OF ANALGESIC NEPHROTOXICITY 529 DISCUSSION To study the modulation of protein expression at the tissue level and in biofluids, we have chosen to evaluate a model of analgesic nephropathy utilizing PAP, a toxicant known to cause necrosis of the renal PST (Green et al, 1969;Davis et al, 1983;Fowler et al, 1994;Harmon et al, 2005). This work followed the dose-and time-dependent progression of ATN lesions and protein expression changes that correlated with morphological stages of injury.…”

Section: Cleaved Caspasementioning

confidence: 99%

Clinicopathological and Tissue Indicators of Para-Aminophenol Nephrotoxicity in Sprague–Dawley Rats

Yang¹,

Trajkovic

Illanes³

et al. 2007

Toxicol Pathol

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A model of para-aminophenol (PAP) nephrotoxicity in Sprague-Dawley rats was utilized to characterize potential indicators of toxicity in the kidney and in biofluids, and to chronicle the progression of acute renal injury. Rats were administered PAP at a low or high dose and examined terminally at 6, 24 and 48 hours (4 animals/group with matching controls). Acute tubular necrosis was observed in the medullary rays (low and high doses) and the outer stripe of outer medulla (high dose only) as early as 6 hours postdosing. Starting at 24 hours, regeneration of the tubular epithelium was evident in both low and high dose studies. Associated with the tubular lesions, we observed elevation of urinary α-glutathione S-transferase levels, an indicator of proximal tubular injury. By immunohistochemistry of the kidney, decreased γ -glutamylcysteine synthetase expression correlated with tubular injury, especially at high dose, whereas elevation of vimentin, osteopontin, and Ki-67 expression was concurrent with tubular regeneration. Clusterin and kidney injury molecule-1 displayed expression patterns characteristic of both renal injury and regeneration. Taken together, this study provided insight into the progression of nephrotoxicity, and allowed the evaluation of potential urinary and tissue protein biomarkers that could complement the early detection of acute tubular injury.

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Role of Contrast Media on Oxidative Stress, Ca2+ Signaling and Apoptosis in Kidney

et al. 2012

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Contrast media (CM)-induced nephropathy is a common cause of iatrogenic acute renal failure. The aim of the present review was to discuss the mechanisms and risk factors of CM, to summarize the controlled studies evaluating measures for prevention and to conclude with evidence-based strategies for prevention. A review of the relevant literature and results from recent clinical studies as well as critical analyses of published systematic reviews used MEDLINE and the Science Citation Index. The cytotoxicity induced by CM leads to apoptosis and death of endothelial and tubular cells and may be initiated by cell membrane damage together with reactive oxygen species (ROS) and inflammation. Cell damage may be aggravated by factors such as tissue hypoxia, properties of individual CM such as ionic strength, high osmolarity and/or viscosity. Clinical studies indeed support this possibility, suggesting a protective effect of ROS scavenging with the administration of N-acetylcysteine, ascorbic acid erdosteine, glutathione and bicarbonate infusion. The interaction between extracellular Ca(2+), which plays a central role in intercellular contacts and production of ROS, and the in vitro toxicity of CM was also reviewed. The current review addresses the role of oxidative stress in the pathogenesis of CM in the kidney as well as current and potential novel treatment modalities for the prevention of neutrophil activation and CM-induced kidney degeneration in patients. ROS production through CM-induced renal hypoxia may exert direct tubular and vascular endothelial injury. Preventive strategies via antioxidant supplementation include inhibition of ROS generation or scavenging.

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Time-dependent effect of p-Aminophenol (PAP) toxicity in renal slices and development of oxidative stress

Cited by 28 publications

References 24 publications

Contribution of reactive oxygen species to para-aminophenol toxicity in LLC-PK1 cells

Contribution of reactive oxygen species to para-aminophenol toxicity in LLC-PK1 cells

Clinicopathological and Tissue Indicators of Para-Aminophenol Nephrotoxicity in Sprague–Dawley Rats

Role of Contrast Media on Oxidative Stress, Ca2+ Signaling and Apoptosis in Kidney

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